Diabetes is a metabolic disorder that afflicts tens of millions of people in the developed countries of the world, with many millions more probably affected in underdeveloped nations. Diabetes results from the inability of the body to properly utilize and metabolize carbohydrates, particularly glucose. Normally, the finely-tuned balance between glucose in the blood and glucose in bodily tissue cells is maintained by insulin, a hormone produced by the pancreas which controls, among other things, the transfer of glucose from blood into body tissue cells. Upsetting this balance causes many complications and pathologies including heart disease, coronary and peripheral artery sclerosis, peripheral neuropathies, retinal damage, cataracts, hypertension and coma and death from hypoglycemic shock.
In patients with insulin-dependent diabetes, the symptoms of the disease can be controlled by administering additional insulin (or other agents that have similar effects) by injection or by external or implantable insulin pumps. The "correct" insulin dosage is a function of the level of glucose in the blood. Ideally, insulin administration should be continuously readjusted in response to changes in blood glucose level. However, at present, blood glucose levels can only be determined directly by a blood sample. Unfortunately, since drawing the sample is invasive, blood glucose is usually only determined once daily or less often. As a result, insulin dosage is not optimally coordinated with blood glucose levels and complications can continue to be manifested. It would, therefore, be desirable to provide non-invasive means for more closely monitoring blood glucose levels and coordinating insulin dosages with such levels.
Many attempts have been made to develop a reliable less invasive or non-invasive way to measure blood glucose level. One of the most widely used methods has been measurement of glucose excreted in the urine, which is under certain conditions an indicator of blood glucose concentration. In its most convenient form, a "dipstick", which has been coated with chemical reagents, is dipped into a urine sample. Glucose in the urine then reacts with the chemical reagents on the dipstick to produce a color change which corresponds to the appropriate range of concentration. The level of urine glucose is then correlated with blood levels on the basis of statistical data and previous experience with the specific patient. However, urine testing has presented several drawbacks. Foremost, is the tenuous link between urine glucose level and blood glucose levels. Although general trends in blood levels within a certain range are usually reflected in urine levels, moderate or periodic fluctuations of blood levels may not be reflected in urine content. Therefore, any dosage change made on the basis of urine analysis is not finely-tuned to blood levels. Furthermore, other substances in urine can cause inaccuracy in measurement by interfering with chemical reactions necessary to produce the color change on the dipstick. Finally, like blood sampling, urine analysis can only be performed at relatively widely spaced intervals when the patient produces urine for analysis.
Other systems have been proposed for monitoring blood glucose levels by implanting a glucose sensitive probe into the patient. Such probes have measured various properties of blood or other tissues, including optical absorption, electrochemical potential and enzymatic products. U.S. Pat. No(s). 4,436,094 and 4,704,029 disclose two examples of blood glucose level probes. U.S. Pat. No. 4,436,094 utilizes an implantable electrode which contains a charged carbohydrate species which, in the absence of glucose, is bound to a component of the electrode and does not affect the potential measured by the electrode. In the presence of glucose, however, charged carbohydrate is displaced from the binding component by molecules of glucose, and as a result of its charge, affects the potential measurement by the electrode. The measured potential can then be correlated to the concentration of glucose.
U.S. Pat. No. 4,704,029 discloses an implantable glucose monitor that utilizes a refractometer which measures the index of refraction of blood adjacent to an interface with the transparent surface of the refractometer by directing laser light at the interface to measure the index of refraction of the blood by the amount of radiation reflected at the interface. As the blood glucose concentration increases, the index of refraction of blood increases. By comparing the intensity of the light reflected by the blood with the intensity of light before contact in the blood, glucose concentration can be determined.
Another approach to tying blood glucose levels to insulin dosage has centered around the implantation of pancreatic cells which produce insulin in response to changes in blood glucose levels as shown for example in Altman et al., Diabetes 35:625-633 (1986); Recordi et al., Diabetes 35:649-653 (1986); Amsterdam et al., J. Cell Biol. 63:1037-1056 (1974); Brown et al., Diabetes 25:56-64 (1976); Carrington et al., J. Endocr. 109:193-200 (1986); and Sonerson et al., Diabetes 32:561-567 (1983). Altman et al. were able to maintain normal blood glucose levels in diabetic mice by implanting cells (1) in areas impermeable to antibodies, (2) suppressing the immunogenecity of the implantable cells in tissue culture before the implantation and (3) enclosing the cells in a capsule that was impermeable to antibodies. However, the implantation methods of Altman et al. and others are severely limited by the availability of large enough masses of cells for effective implantation and by the ability to reliably get insulin production over extended periods after implantation.